Abstract
Fluxes in amounts of intracellular calcium ions are important determinants of gene expression1,2,3. So far, Ca2+-regulated kinases and phosphatases have been implicated in changing the phosphorylation status of key transcription factors and thereby modulating their function4,5. In addition, direct effectors of Ca2+-induced gene expression have been suggested to exist in the nucleus2, although no such effectors have been identified yet. Expression of the human prodynorphin gene, which is involved inmemory acquisition and pain6,7, is regulated through its downstream regulatory element (DRE) sequence, which acts as a location-dependent gene silencer8. Here we isolate a new transcriptional repressor, DRE-antagonist modulator (DREAM), which specifically binds to the DRE. DREAM contains four Ca2+-binding domains of the EF-hand type. Upon stimulation by Ca2+, DREAM's ability to bind to the DRE and its repressor function are prevented. Mutation of the EF-hands abolishes the response of DREAM to Ca2+. In addition to the prodynorphin promoter, DREAM represses transcription from the early response gene c-fos. Thus, DREAM represents the first known Ca2+-binding protein to function as a DNA-binding transcriptional regulator.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Bading, H., Ginty, D. D. & Greenberg, M. E. Regulation of gene expression in hippocampal neurons by distinct calcium signaling pathways. Science 260, 181–186 (1993).
Ghosh, A. & Greenberg, M. E. Calcium signaling in neurons: molecular mechanisms and cellular consequences. Science 268, 239–247 (1995).
Hardingham, G. E., Chawla, S., Johnson, C. M. & Bading, H. Distinct functions of nuclear and cytoplasmic calcium in the control of gene expression. Nature 385, 260–265 (1997).
Sheng, M., Thompson, M. A. & Greenberg, M. E. CREB: a Ca2+-regulated transcription factor phosphorylated by calmodulin-dependent kinases. Science 252, 1427–1430 (1991).
Dolmetsch, R. E., Lewis, R. S., Goodnow, C. C. & Healy, J. I. Differential activation of transcription factors induced by Ca2+-response amplitude and duration. Nature 386, 855–858 (1997).
Weisskopf, M. G., Zalutsky, R. A. & Nicoll, R. A. The opioid peptide dynorphin mediates heterosynaptic depression of hippocampal mossy fiber synapses and modulates long-term potentiation. Nature 362, 423–427 (1993).
Naranjo, J. R., Mellström, B., Achaval, M. & Sassone-Corsi, P. Molecular pathways of pain: Fos/Jun-mediated activation of the prodynorphin gene through a noncanonical AP-1 site. Neuron 6, 607–617 (1991).
Carrión, A. M., Mellström, B. & Naranjo, J. R. PKA-dependent derepression of the human prodynorphin gene via differential binding to an intragenic silence element. Mol. Cell. Biol. 18, 6921–6929 (1998).
Nakayama, S. & Kretsinger, R. H. Evolution of the EF-hand family of proteins. Annu. Rev. Biophys. Biomol. Struct. 23, 473–507 (1994).
Dizhoor, A. M.et al. Recoverin: a calcium sensitive activator of retinal rod guanylate cyclase. Science 251, 915–918 (1991).
Hernández-Cruz, A., Salsa, F. & Adams, P. R. Subcellular calcium transients visualized by confocal microscopy in a voltage-clamped vertebrate neuron. Science 147, 858–862 (1990).
Ehrlich, B. E., Kaftan, E., Bezprozvannaya, S. & Bezprozvannaya, I. The pharmacology of intracellular Ca2+-release channels. Trends Pharmacol. Sci. 15, 145–149 (1994).
Morgan, J. I. & Curran, T. Role of ion flux in the control of c-fos expression. Nature 322, 552–555 (1986).
Sassone-Corsi, P., Sisson, J. C. & Verma, I. M. Transcriptional autoregulation of the proto-oncogene fos. Nature 334, 314–319 (1988).
Deisseroth, K., Heist, E. K. & Tsien, R. W. Translocation of calmodulin to the nucleus supports CREB phosphorylation in hippocampal neurons. Nature 392, 198–202 (1998).
Johnson, C. H., Hill, C. S., Clawla, S., Treisman, R. & Bading, H. Calcium controls gene expression via three distinct pathways that can function independently of the Ras/mitogen activated protein kinase (ERKs) signaling cascade. J. Neurosci. 17, 6189–6202 (1997).
Corneliussen, B.et al. Calcium/calmodulin inhibition of basic-helix-loop-helix transcription factor domains. Nature 368, 760–764 (1994).
Stegh, A.et al. DEDD, a novel death effector domain-containing protein, targeted to the nucleolus. EMBO J. 17, 5974–5986 (1998).
Acknowledgements
We thank N. S. Foulkes for critical reading of the manuscript and I. DomPablo and D. Campos for technical assistance. Work in this laboratory is supported by grants from DGICYT, CAM, Europharma SA and Janssen-Cilag SA (to J.R.N.).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Carrión, A., Link, W., Ledo, F. et al. DREAM is a Ca2+-regulated transcriptional repressor. Nature 398, 80–84 (1999). https://doi.org/10.1038/18044
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/18044
This article is cited by
-
Excitation–transcription coupling, neuronal gene expression and synaptic plasticity
Nature Reviews Neuroscience (2023)
-
Calcineurin Signalling in Astrocytes: From Pathology to Physiology and Control of Neuronal Functions
Neurochemical Research (2023)
-
Calmodulin7: recent insights into emerging roles in plant development and stress
Plant Molecular Biology (2021)
-
Wilm’s tumor 1 promotes memory flexibility
Nature Communications (2019)
-
Targeting the neuronal calcium sensor DREAM with small-molecules for Huntington’s disease treatment
Scientific Reports (2019)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.